STAT6 is an essential transcription factor in the IL-4/IL-13 signaling pathways and the central driver of TH2 inflammation in allergic diseases. Multiple gain of function mutations of STAT6 were identified to cause severe allergic diseases in humans. Dupilumab, an injectable monoclonal antibody that blocks IL-4/IL-13 signaling, is an approved therapy for multiple allergic diseases. STAT6 targeting is therefore supported by both human genetics and clinical pathway validation. STAT6 functions through protein-protein and protein-DNA interactions and it has been challenging to selectively and potently inhibit STAT6 with small molecule inhibitors. However, it is well suited for a targeted protein degradation approach, where a binding event is sufficient to drive degradation. In preclinical studies, KT-621, Kymera’s first-in-class oral STAT6 degrader, demonstrated full inhibition of the IL-4/IL-13 pathway in all relevant human cell contexts with picomolar potency that was superior to dupilumab, and equivalent or superior efficacy to dupilumab in multiple preclinical efficacy studies. In addition, at low oral doses, KT-621 demonstrated near full in vivo STAT6 degradation and was well-tolerated in multiple preclinical toxicity studies.

IRF5, a historically undrugged transcription factor, is a master regulator of innate and adaptive immune response pathways involving pro-inflammatory cytokines (TNFα, IL-6, IL-12, IL-23), B cell activation (autoantibody production), and Type I Interferon (IFN). IRF5 is selectively expressed and activated in specific cell types such as dendritic cells, monocytes, macrophages, and B cells. Its cell- and disease activation-specific profile has the potential to block cell-specific immune dysregulation while sparing normal cell function. IRF5 has been challenging to drug using traditional small molecule inhibitors due to multiple complex activation steps and the high degree of IRF family member homology. KT-579, a potent, selective oral degrader, has the potential to be the first IRF5-targeted therapy. In preclinical studies KT-579, degraded IRF5 across multiple preclinical species and in all disease-relevant tissues. In preclinical models of lupus and RA, KT-579 was equal or more efficacious than clinically active or marketed small molecule inhibitors and biologics. In preclinical safety studies, KT-579 did not show any adverse effects at concentrations up to 200-fold of the projected human efficacious levels. KT-579 has the potential for broad utility in diseases where effective and well tolerated oral therapies are needed.

KT-474 is a first-in-class IRAK4 degrader in development for the treatment of immune-inflammatory diseases with significant patient need, such as hidradenitis suppurativa (HS), atopic dermatitis (AD), and potentially others. IRAK4 is a key protein of the myddosome complex that mediates signaling through IL-1 and toll-like receptors, which play a crucial role in initiating the immune response against invading pathogens. IRAK4 is a scaffolding kinase that acts at the interface of the innate and adaptive immune responses with a variety of functions depending on its kinase activity and scaffolding function. Eliminating IRAK4 completely through degradation impacts both the kinase and scaffolding functions, therefore having the potential to achieve a broad, well-tolerated, anti-inflammatory effect providing a novel therapeutic approach for a variety of immune-inflammatory diseases.

KT-474 (SAR444656) is partnered with Sanofi, who is leading the Phase 2 clinical development program. Kymera has the option to participate in future development and commercialization, and 50/50 profit split, in the United States. Double digit tiered royalties in ROW.

Diseases where the TLR/IL-1 pathway has been implicated in pathogenesis and are potential opportunities: Psoriasis, Generalized Pustular Psoriasis, IBD, Asthma, COPD, SSc ILD, RA, PSA, SLE, OA, PSS, MS, AMD.